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IMPURITY PROFILING: OVERVIEW ON IMPURITY PROFILING AND REPORTING

METHODOLOGIES ADOPTED BY UNITED STATES AND EUROPE

Article  in  World Journal of Pharmaceutical Research · November 2017

DOI: 10.20959/wjpr201714-9863

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 World Journal of Pharmaceutical Research
Rawat et al. World Journal of Pharmaceutical
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Impact Factor 7.523

Volume 6, Issue 14, 206-221. Review Article ISSN 2277–7105

IMPURITY PROFILING: OVERVIEW ON IMPURITY PROFILING

AND REPORTING METHODOLOGIES ADOPTED BY UNITED
STATES AND EUROPE

Shashank Rawat1* and Vijay Kumar2

1
Regulatory Affairs Officer, Ind Swift Laboratories Ltd, Panchkula-134102.
2
Drug Regulatory Affairs, School of Pharmaceutical Sciences, Lovely Professional
University, Phagwara-144 001.

Article Received on ABSTRACT

04 Sept. 2017, Impurities are not acceptable in drug formulation. It is considered as
Revised on 25 Sept. 2017,
Accepted on 15 October 2017 unwanted chemicals or organic material which remains with Active
DOI: 10.20959/wjpr201714-9863 Pharmaceutical Ingredient (API’s). The impurity is produced either
during formulation or ageing of both API’s and finished dosage form.
*Corresponding Author The existence of these undesired chemicals may influence the safety
Shashank Rawat and the efficacy of the pharmaceutical finished products. In this review
Regulatory Affairs Officer,
article we have discussed about the methodologies adopted by United
Ind Swift Laboratories Ltd,
States and Europe for Impurity profiling given by their respective
Panchkula-134102.
regulatory authorities. Impurity profiling, calculation and
methodologies used to represent impurities in dossier regulation related documents.

KEYWORDS: Impurity, Residual Solvent, API, SFC.

INTRODUCTION
The impurity profile has become essential as per various regulatory requirements. For the
pharmaceutical industries impurity is considered as organic material or unwanted chemicals
which remain with Active Pharmaceutical Ingredient (API’s). The impurity be developed
either during formulation or ageing of both API’s and Formulation. The presence of these
unwanted chemicals may influence the efficacy and the safety of the pharmaceutical
products. Impurity profiling gaining more attention from regulatory authorities. The impurity
profiling is the description of identified and unidentified impurities present in new drug

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Rawat et al. World Journal of Pharmaceutical Research

substance. Some impurities have been named as per International Conference on

Harmonization (ICH) such as.[1]
 By-products.
 Degradation products.
 Interaction products.
 Intermediates.
 Related products.
 Transformation products.

Impurity: “It is defined as any substance coexisting with the original drug, such as starting
material, intermediate, and any side reactions”.

OR
It is the unwanted chemicals substance which influences the safety and efficacy of the
pharmaceutical products.[2]

Profiling: It is the process of the identification through which we get the characteristic of the
substance.[3]

Impurity Profiling: It is the process of evaluating the data that establish biological safety of
an individual impurity. For maintaining the stability or efficacy of the API we do the
profiling of impurities. It helps in identifying and quantifying the impurities in API. It gives
maximum possible types of impurities present in drug substance (API) and in pharmaceutical
formulations. The impurity control in the pharmaceutical product is the main goal of the drug
development and for controlling the impurity, there are various regulatory guidelines which
monitored the impurities in API.[4]

Classification of impurities in API

As per the ICH guidelines, the impurities are classified in three types as below.
1. Organic impurities (process and drug related).
2. Inorganic impurities.
3. Residual solvents.

Organic impurities: These impurities are classified as starting material, By-product,

degradation product, reagents and chiral impurities.

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a) Starting materials: The impurities from the starting material or by product are found in
every drug substance, so for that proper care should be done to remove that impurities before
it effect the end product. For e.g. In the synthesis of baclofen, the last step is carried out with
gutarimide, after which on reaction with sodium hydroxide solution at room temperature it
yield a potential impurity i.e. p-chloro phenyl gluteric acid.

b) By-products: There is always a chance of having by-products. Because they can be

formed through avariety of side reactions, such as incomplete reaction, over reaction,
isomerization, dimerization, rearrangement or unwanted reaction between starting materials
or intermediate with the chemical reagents or catalysts. For e.g. In the case of Paracetamol
bulk production, diacetylated Paracetamol may form as a by-product.

Inorganic impurities: Inorganic impurities are derive from the manufacturing processand
excipients. Inorganic impurities mainly include water, salts from buffers, reagents, ligands,
catalysts, heavy metals, or other residual metals and also the inorganic compounds used in the
processing such as filter aids and charcoal.
 Reagent, ligand and catalyst: The chances of these impurities are rare but these impurities
could create a problem so proper care has to be taken during production. For e.g. chloride.
 Heavy metals: The main sources of the heavy metals are, the reactors where acidification
and acid hydrolysis takes place. The impurities which are arising due to the heavy metals,
that can easily be avoided by demineralized water and by using glass lined reactors. For
e.g. water.
 Filter aids and charcoal: These are the centrifuge bags which are routinely used in the
bulk drugs manufacturing plants. For e.g. activated carbon.

Residual solvents: These are the undesirable substance. They modify the properties ofcertain
compounds or may be hazardous for the human health. These solvents also affect
thephysicochemical properties of the bulk drug such as crystallinity of the bulk drug.
As per ICH guidelines, the solvents are classified into three categories:
1. Class 1 solvent: These solvents are not employed in the manufacture of drug substances,
excipients and formulations because of their unacceptable toxicity or their deleterious
effects Table.1.
2. Class 2 solvent: these solvents have limited use in the pharmaceutical products because of
their inherent toxicity Table.2.

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3. Class 3 solvents: these are the less toxic and possess lower risk to the human health.
These solvents do not have any serious hazardous Table.3.

Table 1: Class 1 Solvents to be avoided in pharmaceutical products.[5]

Solvent Concentration limit(ppm) Concern
Benzene 2 Carcinogen
CCl4 4 Toxic and environmental hazard
1,2-Dichloroethane 5 Toxic
1,1-Dichloroethane 8 Toxic
1,1,1-Trichloroethane 1500 Environmental hazard

Table 2: Class 2 solvents to be limited in pharmaceutical products.

Solvent PDE(mg/day) Concentration limit(ppm)
Acetonitrile 4.1 410
Chloroform 0.6 60
Cyclohexane 38.8 3880
Ethylene glycol 6.2 620
Formamide 2.2 220
Hexane 2.9 290
Methanol 30.0 3000

Table 3: Solvents for which no adequate toxicological data was found.[5]

1,1-Diethoxypropane Methyl isopropyl ketone
1,1-Dimethoxymethane Methyltetrahydrofuran
2,2-Dimethoxypropane Petroleum ether
Isooctane Trichloroacetic acid
Isopropyl ether Trifluoroacetic acid

Impurities present in formulation

Number of impurities in a drug product can arise from ingredients which are used for the
product formulation. In the process of formulation there are varieties of conditions that can
lead degradation or other deleterious reaction. In the formulation use of water cannot only
contribute its own impurities but it is also provide a ripe situation for the hydrolysis and
catalysis.[6]

Impurity forms during formulation are.

a) Method related.
b) Environmental related.

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The primary environmental factors that can reduce stability include the following.
 Exposures to adverse temperatures.
 Light-especially UV light.
 Humidity.

c) Dosage form related impurities.

A) Mutual interaction amongst ingredients.
B) Functional group- related typical degradation.
 Ester hydrolysis
 Hydrolysis
 Oxidative degradation
 Photolytic cleavage
 Decarboxylation

Method related impurity: This is the impurity which is related from method. For e.g. in the
production of the parental dosage form of diclofenac sodium, Indolin-2-one is the impurity
formed during the sterilization by autoclave. During the autoclave condition, the formation of
indolinone derivative and sodium hydroxide takes place due to the intramolecular cyclic
reaction of the diclofenac sodium.[6]

Environmental related impurities: Environment related factors are the factors which that
reduce the stability of the drug substance such as.
 Exposure to adverse temperature: Many of the drug substance are heat sensitive in nature.
For e.g. vitamins are very heat sensitive in nature due to which they undergo degradation
in liquid formulation that cause the decrease in potency of vitamin.
 Light especially UV light: This light makes unstable to the drug substance. For e.g.
Ergometrine and methyl ergometrine injection is unstable or shows the complete
degradation when kept in the direct sunlight.
 Humidity: It affect the hygroscopic products, which are sensitive in the humid
environment. It affect the bulk powder and solid dosage form for e.g. Aspirin and
Ranitidine.

Dosage form related impurities: Sometimes the dosage form factors that influence the
stability of the drug. In general, liquid dosage forms are much susceptible to both degradation

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and microbial contamination. In which, water content, pH of the solution, compatibility of the
anions and cations, mutual interaction of the ingredients, and the primary containers are the
critical factors for the impurities.

a) Mutual interaction amongst ingredients.

Mutual interaction among the ingredient is also the major problem which cause the instability
in the drug product. Most of the vitamins are very liable and on storing they pose a problem
of instability in different dosage form but especially in the liquid dosage form. For e.g. during
the formulation, one formulation is in simple distilled water and other is in typical formulated
vehicle that include disodium edetate and benzyl alcohol both have similar mutual interaction
causing the degradation of the product.
b) Functional group related typical degradation.

Ester hydrolysis: It is the reaction when the ester reacts with the water to produce ethanoic
acid and ethanol.

Hydrolysis: It is a reaction which occurs due to water. Mainly this is a reaction of breaking
bond in a molecule by using water. For e.g. sodium acetate is a salt which get hydrolyze by
adding water and then separate in to the sodium ions and acetate ions.

Oxidative degradation: It is the degradation in which the cleavage of c=c with the
introduction of new carbon and oxygen bond. For e.g. hydrocortisone, methotrexate,
conjugated dienes, nitrite derivatives and aldehydes all are susceptible to the oxidative
degradation.

Photolytic cleavage: it occurs due to the direct exposure of the sunlight. For e.g. in the
preparation of ciprofloxacin eye drop, sunlight induce the photocleavage reaction producing
ethylenediamine analog of ciprofloxacin.

Decarboxylation: In this case when we heat the p-aminosalicylic acid then it lose the carbon
dioxide from the carboxyl group. Decarboxylation also occurred in the case of photoreaction
of rufloxacin.[1]

Impurities present in raw material

It is the impurities present in the raw material which contaminate the final product. These
impurities are Arsenic, lead heavy metals etc all are present in the raw materials. For e.g.

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Rock salts contain small amount of calcium and magnesium chloride, so the sample of Nacl
is likely to contain traces of calcium and magnesium as a impurity. Sodium compounds are
prepared from Nacl due to low cost and easy availability, in which Cl is present as an
impurity.

Identification of impurities[1]
The impurities can be identified by the following methods.
 Reference standard method
 Spectroscopic method
 Separation method
 Isolation method

Reference standard method: It is the method in which reference standard prepared for use
as the standard in an assay, identification, or purity test. By this method we can evaluate both
the process and product performance. It is not only gives the information for the active
ingredient in dosage form but also for the impurities, degradation product, starting materials,
and excipients.

Spectroscopic method: The UV, IR, MS, NMR, and Raman spectroscopic methods are
routinely being used for characterizing the impurities.
a) Ultraviolet spectrometry: It is a physical technique of the spectroscopy that uses light. It
is determine the concentration of the absorber in a solution. By rapidly change in the
absorbance we can determine the impurity.
b) Infrared spectroscopy: It is used in the research to identify samples, do quantitative
analysis, or detect impurities. It can be used on solid, liquid or gaseous samples and also
does not destroy the sample in the process.
c) Mass spectrometers: It provides the accurate mass measurements of a sample molecules,
sample identification, and quantitation of the samples. It can be used with GC-MS and
LC-MS. It is a combine feature of gas and liquid chromatography.
d) NMR Spectroscopy: It is very sophisticated system which is based on the use of nuclear
magnetic resonance technology. It is used to test atomic and molecular properties of the
sample. It is very sensitive in nature.[1]
e) Raman spectroscopy: It is used to study vibrational, rotational and other low frequency
modes in a system. It is fairly good sensitivity and detect the process related impurities.

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Separation method: The following separation methods are as follows.

a) Thin-layer chromatography: It is a chromatography technique which is used to separate
the mixtures. It is performed on the sheet of the glass, plastic, and aluminum foil which is
coated with the adsorbent material such as silica gel, aluminum oxide and cellulose. After
the sample has been applied on the plate then a solvent mixture is drawn up by the
capillary action. After some time the mixture gets separate.
b) Gas chromatography: It is a common type of chromatography which is used for
separating and analyzing the compounds. Mainly it is of two types’ i.e Gas-Liquid
chromatography and Gas chromatography. Most of the time gas chromatography is used
for the testing of purity or separating the different components of the mixtures. It is
helpful in the preparation of the pure compounds from the mixtures.
c) High-pressure liquid chromatography: It is a column chromatography used to separate,
identify, and quantify the compounds. HPLC have different type’s stationary phases and a
pump that moves the mobile phase and also there is a detector to provide the
characteristic information about the compound such as API and its impurities. It is helpful
to check the quality of the API starting material and also signify the unknown impurities.
d) Capillary electrophoresis: It is also known as capillary zone electrophoresis. It is used to
separate the ionic species by their charge and size in the small capillary filled inside with
an electrolyte. It is based on the different separation principles and also used for the
quality control of the pharmaceutical products.
e) Supercritical fluid chromatography (SFC): It is the chromatography in which we
separate one component from other component by using the super critical fluid. Carbon
dioxide is used as a supercritical fluid where ethanol or methanol used as a co-solvent. In
this we provide the critical temperature of 31oc with critical pressure of 72 bars.

Isolation method: It is necessary to isolate the impurities. Generally chromatographic and

non-chromatographic techniques are used for the isolation of the impurities. There are
various methods by which we can isolate the impurities such as.
a) Solid-phase extraction method: It is the method which is used to trace the organic
compound as well as remove the interfering compound to obtain a clear extract. Mainly
this technique is used for the extraction and purification of the compounds. Main use of
this method is to clean up the sample before use for the chromatographic technique to
quantify the analyte in the sample. This technique is widely applied for the isolation of
analytes from a liquid matrix.

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b) Liquid-liquid extraction method: It is also known as solvent extraction and partitioning.

It is a method which is used to separate compounds based on their relative solubility’s in
two different immiscible liquids usually water and organic solvents. The method is
perform in the separating funnel. Commonly solvents used for liquid-liquid extraction are
ethyl acetate, methylene chloride and hexanes.
c) Accelerated solvent extraction method: It is the better technique used for the extraction
of solid and semi-solid samples. All the process done at the elevated temperature and
pressure to get the fast and efficient removal of analysts from the samples. It perform the
experiment in less time with using smaller quantity of solvent.

Regulatory bodies involved in impurity profiling

There are various regulatory authorities like ICH, USFDA, EMA, CDSCO and Canadian
drug and health agency for the identification of impurities in active pharmaceutical
ingredients. Such regulatory authorities are discussed below.

ICH: It stand for International Conference on Harmonization. It is for the registration of

pharmaceuticals for human use. ICH is unique in bringing together the regulatory authorities
and pharmaceutical industry to discuss scientific and technical aspect of drug registration.
ICH’s mission is to achieve greater harmonization to ensure safe, effective, and high quality
medicines are developed and registered in the most efficient manner. These activities have
been under taken to promote the public health, prevent unnecessary duplication of clinical
trials in humans and minimize the use of animal testing without compromising safety and
effectiveness. ICH divides its guidelines into four categories such as.[7]

Quality guidelines: For achieving quality they conduct stability studies, relevant threshold
for impurity testing and more flexible approach to the pharmaceutical quality based on good
manufacturing practice.

Safety guidelines: ICH produced comprehensive guidelines for achieving the safety and
reduce the potential risk such as carcinogenicity, genotoxicity and reprotoxicity.

Efficacy guidelines: For the efficacy it concern with the design, conduct, safety and
reporting of clinical trials. And it also covers the novel types of medicines derived from
biotechnological process. The main aim is to produce better targeted medicines.

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Multidisciplinary guidelines: It is different from quality, safety, and efficacy. It includes

ICH medical terminology, and the common technical document.[8]

USFDA: It stand for U.S Food and Drug Administration. Mainly FDA is responsible for
protecting the public health by assuring the safety, efficacy and security of human and
veterinary drugs, biological products, medical devices, cosmetics and product that emit
radiation. It also have a responsibility for regulating the manufacturing, marketing and
distribution of tobacco product to prevent the human health and to reduce the tobacco use. It
play a significant role in the Nation Counterterrorism. The FDA’s fulfills these
responsibilities by ensuring the security of the food supply and by fostering the development
of medical products for the public health. The regulatory authority is very broad. They
regulate foods including dietary supplements, food additives, and other food products. For
drug they regulate prescription and non-prescription drugs. For biologics they regulate
vaccines, blood and blood products etc. Another they regulate medical devices, cosmetics,
veterinary products, tobacco products etc. USFDA is the oldest comprehensive protection
agency in the U.S federal government.[9]

The organization of FDA consists

 Office of the Commissioner
 Office of Foods and Veterinary Medicine
 Office of Global Regulatory Operations and Policy
 Office of Medical Products and Tobacco
 Office of Operations[10]

EMA: Mainly it stand for European Medicines Agency. It is a decentralized agency of the
European Union, located in London. This is the agency which is responsible for the scientific
evaluation of the medicines developed by the pharmaceutical companies. The main
responsibilities of the European Medicines Agency is the protection and promotion of the
public health and animal health, which is done through the evaluation and supervision of
medicines for human and veterinary use. The agency is responsible for the scientific
evaluation of application for the European Union market Authorization for the human and the
veterinary medicines.

Most of the scientific evaluation work is carried out by its own scientific committees which
are made up members of EEA countries, as well as representative of patient, consumer and

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healthcare professionals’ organizations. There are various related tasks to the development,
assessment, and supervision of medicines in the EU which is done by these committees.

The EMA is responsible for the coordinating safety-monitoring or pharmacovigilance system

for the medicines. It monitors the safety of medicines through the EU network and up on the
information of benefit-risk balance of medicines they can take the action and has changed
since it was authorized. This agency works.
 This agency provides the specific report to pharmacovigilance activities for centrally
authorized product.
 Fee developing guidelines and setting standards.
 Coordinating to monitoring the pharmaceutical companies with their pharmacovigilance
obligations.
 It informing all the public about the safety of the medicines and interact with the
representatives of patients and healthcare professionals.[11]

The agency is also responsible for coordinating inspections such as.

 Good manufacturing practice, (GMP)
 Good clinical practice, (GCP)
 Good laboratory practice, (GLP)
 Pharmacovigilance, ( Phv)

The European Medicine Agency does not control[12]

 The price of the medicines.
 Patents on medicines.
 The availability of the medicines.
 Medical devices.
 Homeopathic medicines.
 Herbal supplements.
 Food supplements.
 Cosmetics.
 Advertisement of medicines.

Guidelines given by regulatory authorities for Impurity Profiling

The impurity profiling guidelines are given by the ICH which is common for all the regulated
and semi regulated countries. But it is not mandatory to follow the ICH guidelines; different

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regulatory agencies can follow their own guidelines also. But for obtaining the good result in
impurity profiling it is good to follow the guidelines which are given by the ICH.

ICH Q3AR guideline for the impurity testing in new drug substances. This guideline provides
the guidelines for registration application on the content and qualification of impurities in
new drug substances produced by chemical synthesis. Specification should include.

Organic impurities
Each specified identified impurity.
Each specified unidentified impurity.
Any unspecified impurity.
Total impurities.

Each specified identified impurity are those impurity which are listed with a specific
acceptance criterion in the new drug substance or which is easily identified. Each specified
unidentified impurity which is not more than identification threshold Table.3.

Table No 3: Threshold values

Maximum Reporting Identification Qualification
Daily Dose Threshold Threshold threshold
0.10% or 1.0 mg/day 0.15% or 1.0 mg/day
<2g/day 0.05% intake (whichever is intake (whichever is
lower) lower)
> 2g/day 0.03% 0.05% 0.05%

The threshold limit is based on scientific data including drug class effects and clinical
experience. These threshold limits are either lower or higher can be. Such as given below.
-Adverse reaction in patients
-Patient population
-Drug class effect
-Clinical experience

The whole study will depend up on the number of factors like.

 Patient population
 Daily does
 Routes and duration of drug administration.[13]

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As according to different countries they provide the different guidelines on the impurity
profiling. Such are discussed below.

United States for Food and Drug Administration: USFDA addressed the impurities in new
drug substance as by chemical aspects and safety aspects. Mainly they follow the guidelines
of ICH for the impurity profiling. Threshold values are shown in Table.4.[13]

Table 4: Threshold values.

Maximum Reporting Identification Qualification
Daily Dose Threshold Threshold Threshold3
0.10% or 1.0 mg per day 0.15% or 1.0 mg per day
≤ 2g/day 0.05% intake (whichever is intake (whichever is
lower) lower)
>2g/day 0.03% 0.05% 0.05%

Table No 4a.
Calculated Total Daily
Reported Result Identification Qualification
Raw” Action Intake
(%) (Threshold (Threshold
Result (TDI) (mg) of the
Reporting 0.10% 0.15%
(%) impurity
threshold =0.05% (exceeded?) (exceeded?)
(rounded result in mg)
0.044 Not reported 0.2 None None
0.0963 0.10 0.5 None None
0.12 0.12 0.6 Yes None
0.1649 0.16 0.8 Yes Yes

Table No 4b.
Reported Calculated Total
Result Daily Intake Identification Qualification
“Raw”
(%) (TDI) (mg) (Threshold (Threshold 1.0
Result
Reporting of the impurity 0.10% mg TDI
(%)
threshold (rounded result in (Exceeded?) (Exceeded?)
=0.05% mg)
0.066 0.07 0.6 None None
0.124 0.12 1.0 Yes None
0.143 0.14 1.1 Yes Yes

In USFDA, attachment 1 is similar as ICH where attachment 2 is differs from EMA.

European Medicines Agency: There is draft version for the impurity profiling in case of
antibiotics. They developed guidelines for the impurities in antibiotic that are fermented
products or semi synthetic substance. Therefore they are not included in the ICH guideline.

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EMA will depend on the European pharmacopeia which is also abbreviated as Ph. Eur. This
contain monograph which tells about the substance manufactured by fermentation not by the
semi-synthesis. The general consideration for the impurity thresholds in antibiotic through
fermentation, these are present in this guideline. For the antibiotic drug substances, the
impurity profile should be characterized according to the guidance described in ICH 3QA
(VICH GL10).

In according with that guidance limits should be set for.

 Each specified identified impurity
 Each specified unidentified impurity
 Any unspecified impurity
 Total impurities

For the different types of antibiotics thresholds are given below.

 Active substance manufactured by semi-synthesis.
For active substance used in veterinary medicines threshold for reporting, identification and
qualification are 0.10%, 0.20% and 0.50%, respectively.

 Active substance manufactured by fermentation, single compound.

Reporting threshold: 0.10%
Identification threshold: 0.15%
Qualification threshold: 0.15%

 For active substance used in veterinary medicines.

Reporting threshold:0.10%
Identification threshold: 0.20%
Qualification threshold: 0.20%

 Active substances manufactured by fermentation, family of compounds.

Reporting threshold: 0.10%
Identification threshold: 0.15%
Qualification threshold: 0.50%/0.15%

 For active substance used in veterinary medicines.

Reporting threshold: 0.10%.
Identification threshold: 0.20%.

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Rawat et al. World Journal of Pharmaceutical Research

Qualification threshold: 0.50%.

 Active substance manufactured by semi-synthesis.

Reporting threshold: 0.1%.
Identification threshold: 0.2%.
Qualification threshold: 0.2%.

 Active substance manufactured by fermentation, single compound.

Reporting threshold: 0.15%.
Identification threshold: 0.2%.
Qualification threshold: 0.2%.

 Active substance manufactured by fermentation, family of compound.[14]

Reporting threshold: 0.15%.
Identification threshold: 0.2%.
Qualification threshold: 0.5%/0.2%.

CONCLUSION
From this review we conclude that, it is mandatory requirements in various pharmacopoeias
to know the impurities present in API’s and Formulation. Isolation and characterization of
impurities is required for acquiring and evaluating data that establishes biological safety
which reveals the need and scope of impurity profiling of drugs in pharmaceutical research.
To isolate and quantify the impurities, various instrumental analytical techniques are
routinely been used. We conclude that both United States and Europe having well established
guidelines for impurity identification and specified limits for control impurity in API and
Formulation.

ACKNOWLEDGEMENT
The authors are thankful to the Guide, Suraj Pal Verma, School of Pharmaceutical Sciences,
Lovely Professional University, Punjab, India for useful discussion and support.

REFERENCES
1. Bari S. Impurity profile significance in Active Pharmaceutical Ingredient; Eurasian
journal of Analytical Chemistry, 2007; 2: 32-53.
2. https://www.webmedcentral.com/article_view/2884.
3. http://www.thefreedictionary.com/profile.

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4. Tegeli S. Significance of Impurity Profiling; International Journal of Drug Formulation

and Research, 2011; 2: 174-194.
5. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3C/S
tep4/Q3C_R5_Step4.pdf.
6. Pawale S. Impurity Profile in Bulk Drugs and Pharmaceutical Preparation; International
Journal of Pharmaceutical and Chemical Sciences, 2012; 1(4): 1227-1237.
7. http://www.ich.org/products/guidelines.html.
8. http://www.ich.org/products/guidelines.html.
9. http://www.fda.gov/AboutFDA/WhatWeDo/default.htm.
10. http://www.fda.gov/AboutFDA/CentersOffices/
11. http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/general/general_content_0
00091.
12. http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/q_and_a/q_and_a_detail_
000114.jsp#section1.
13. ICH guideline Q3A (R) for impurities testing in New Drug Substance.
14. European Medicines Agency guideline for impurities in Antibiotics.

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